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1 Experimental Cardiology, Thoraxcentre, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Abstract |
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-nitro-L-arginine, 20 mg kg–1
I.V.) and/or cyclo-oxygenase (indometacin, 10 mg kg–1
I.V.). In the systemic circulation, ET receptor blockade decreased vascular resistance at rest, which waned with increasing exercise intensity. Prior inhibition of either NO or prostanoid production augmented the vasodilator effect of ET receptor blockade, and these effects were additive. In contrast, in the pulmonary bed, ET receptor blockade had no effect under resting conditions, but decreased pulmonary vascular resistance during exercise. Prior inhibition of NO synthase enhanced the pulmonary vasodilator effect of ET receptor blockade, particularly during exercise, whereas inhibition of prostanoids had no effect, even after prior NO synthase inhibition. In conclusion, endogenous endothelin limits pulmonary vasodilatation in response to treadmill exercise. This vasoconstrictor influence is blunted by NO but not by prostanoids.
(Received 6 July 2005;
accepted after revision 28 July 2005;
first published online 4 August 2005)
Corresponding author D. J. Duncker: Experimental Cardiology, Thoraxcentre, Erasmus MC, University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, the Netherlands. Email: d.duncker{at}erasmusmc.nl
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Introduction |
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The vascular endothelium releases a variety of vasoactive substances, including nitric oxide (NO), prostanoids and endothelin (ET), that contribute to vasomotor control. However, the endothelial lining is not a homogeneous compartment as it is characterized by significant structural and functional heterogeneity. For example, the endo-thelium in the pulmonary bed differs markedly in ultrastructure and function from the systemic endo-thelium (Aird, 2003; Budhiraja et al. 2004). In support of this concept, recent studies in swine indicate that while both NO and prostanoids exert a vasodilator influence on the systemic vascular bed during exercise, only NO, but not prostanoids, contributes to the exercise-induced pulmonary vasodilatation (Duncker et al. 2000; Merkus et al. 2004). Furthermore, we recently observed in exercising swine that in the systemic circulation, the vasoconstrictor influence of ET wanes with increasing exercise intensities, whereas in the pulmonary circulation an ET vasoconstrictor influence emerges during exercise (Merkus et al. 2003). Since ET can increase the production of NO and prostanoids, which in turn can blunt the release of ET (Rubanyi & Polokoff, 1994; Haynes & Webb, 1998; Schiffrin & Touyz, 1998) or modify the responsiveness of its receptors (Wiley & Davenport, 2001), the present study was undertaken to investigate the integrated vasomotor control of pulmonary vascular resistance by NO, prostanoids and ET, in chronically instrumented swine under resting conditions and during graded treadmill exercise.
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Methods |
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Studies were performed in accordance with the Council of Europe Convention (ETS123)/Directive (86/609/EEC) for the protection of vertebrate animals used for experimental and other scientific purposes, and with approval of the Animal Care Committee of the Erasmus Medical Center. Fifteen 2–3-month-old Yorkshire X Landrace swine (22 ± 1 kg at the time of surgery) of either sex entered the study.
Surgery
Swine were sedated with ketamine (30 mg kg–1 I.M.), anaesthetized with thiopental (10 mg kg–1 I.V.), intubated and ventilated with a mixture of O2 and N2O (1: 2) to which 0.2–1% (v/v) isoflurane was added (Stubenitsky et al. 1998; Duncker et al. 2001). Anaesthesia was maintained with midazolam (2 mg kg–1 + 1 mg kg–1 h–1 I.V.) and fentanyl (10 µg kg–1 h–1 I.V.). Under sterile conditions, the chest was opened via the fourth left intercostal space and a fluid-filled polyvinylchloride catheter was inserted into the aortic arch for aortic blood pressure measurement (Combitrans pressure transducers, Braun) and blood sampling. An electromagnetic flow probe (14–15 mm, Skalar) was positioned around the ascending aorta for measurement of cardiac output. Polyvinylchloride catheters were inserted into the left atrium to measure pressure, and into the pulmonary artery to measure pressure, administer drugs and collect mixed venous blood samples. Catheters were tunnelled to the back, and animals were allowed to recover, receiving analgesia (0.3 mg buprenorphine I.M.) for 2 days and antibiotic prophylaxis (25 mg kg–1 amoxicillin and 5 mg kg–1 gentamicin I.V.) for 5 days.
Experimental protocols
Studies were performed 1–3 weeks after surgery with animals exercising on a motor driven treadmill. The excellent reproducibility of consecutive exercise trials has been reported previously (Duncker et al. 1998, 2000, 2001; Stubenitsky et al. 1998). In the present study, four exercise protocols were performed on different days and in random order.
Endothelin. With swine (n = 11) lying quietly on the treadmill, resting haemodynamic measurements, consisting of heart rate, cardiac output, mean aortic pressure (MAP), mean pulmonary artery pressure (MPAP), and mean left atrial pressure (MLAP) were obtained and blood samples collected. Haemodynamic measurements were repeated, and rectal temperature was measured with animals standing on the treadmill. Subsequently, a five-stage (1–5 km h–1) treadmill exercise protocol was started; each exercise stage lasted 2–3 min. Haemodynamic variables were continuously recorded and blood samples collected during the last 45 s of each stage. After completing the exercise protocol animals were allowed to rest on the treadmill for 90 min, after which the mixed ETA and ETB receptor (ETA/ETB) antagonist tezosentan (a gift from Dr Clozel, Actelion Pharmaceuticals Ltd) was intravenously administered over 10 min in a dose of 3 mg kg–1, followed by a continuous infusion of 6 mg kg–1·h–1 I.V. (Merkus et al. 2003), and the exercise protocol was repeated.
Prostanoids and endothelin. Ninety minutes after nine swine had undergone a control exercise trial (as described above), animals received the cyclo-oxygenase inhibitor indometacin ((Sigma) 10 mg kg–1 I.V. over 10 min (Merkus et al. 2004)), and 5 min later underwent a second exercise trial. Ninety minutes later, animals received indometacin in a dose of 5 mg kg–1 I.V., which resulted in haemodynamic conditions that were identical to those following administration of 10 mg kg–1 prior to the second exercise trial. Subsequently, animals received tezosentan (3 mg kg–1 I.V. + 6 mg kg–1 h–1 I.V.), and underwent a third exercise trial.
NO and endothelin.
Ninety minutes after seven swine had undergone a control exercise trial, animals received the NO-synthase inhibitor N-nitro-L-arginine (NLA (Sigma), 20 mg kg–1
I.V.; (Duncker et al. 2000)), and underwent a second exercise trial. Ninety minutes later, animals received tezosentan (3 mg kg–1
I.V.
+ 6 mg kg–1 h–1
I.V.) and underwent a third exercise trial.
NO, prostanoids and endothelin. Ninety minutes after five swine underwent an exercise trial in the presence of NLA (20 mg kg–1 I.V.), animals received indometacin (10 mg kg–1 I.V.) and underwent a second exercise trial. Ninety minutes later, animals received indometacin (5 mg kg–1 I.V.) and tezosentan (3 mg kg–1 I.V. and 6 mg kg–1 h–1 I.V.), and underwent a third exercise trial.
Blood gas measurements
Blood samples were kept in iced syringes until the conclusion of each exercise trial. Measurements of PO2(mmHg), PCO2(mmHg) and pH were then immediately performed with a blood gas analyser (Acid-Base Laboratory Model 505, Radiometer, Copenhagen, Denmark). Oxygen saturation (%) and haemoglobin (g (100 ml)–1) were measured with a haemoximeter (OSM3, Radiometer). Blood O2 content (µmol ml–1) was computed as (Hb x 0.621 x O2 saturation) + (0.00131 x PO2). Body O2 consumption (BVO2) was calculated as the product of cardiac output and the difference in O2 content between arterial and mixed venous blood (Stubenitsky et al. 1998; Duncker et al. 2001).
Data analysis
Digital recording and off-line analysis of haemodynamics have been previously described (Duncker et al. 1998; Stubenitsky et al. 1998). Systemic vascular resistance was computed as mean aortic blood pressure divided by cardiac output. Pulmonary vascular resistance was computed as mean pulmonary artery pressure minus mean left atrial pressure divided by cardiac output (Merkus et al. 2004).
Statistical analysis
Analysis of variance (ANOVA) for repeated measures or analysis of covariance (ANCOVA) were used as appropriate. Post hoc testing for exercise and drug effect was performed using Scheffe's test. Statistical significance was accepted when P < 0.05. Data are presented as mean ± S.E.M.
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Results |
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Systemic circulation. Table 1 shows that exercise up to 5 km h–1 resulted in more than a doubling of cardiac output which was principally due to an increase in heart rate (up to 85% of maximum heart rate), as stroke volume increased by only 15% (not shown). The increase in cardiac output, was balanced by a similar decrease in systemic vascular resistance (Fig. 1), so that mean aortic blood pressure was minimally affected (Table 1).
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Pretreatment with NLA enhanced the indometacin-induced vasoconstriction in the systemic circulation, as indicated by the exaggerated increase in systemic vascular resistance and exaggerated decrease in mixed venous O2 saturation. Importantly, despite the marked potentiation of the systemic vasoconstrictor response to cyclo-oxygenase inhibition by NO synthase inhibition under resting conditions, the exercise-induced vasodilatation was unmitigated in the presence of indometacin and NLA (Fig. 1).
Pulmonary circulation. Pulmonary artery pressure doubled during exercise (Table 1). However, the transpulmonary pressure gradient (MPAP – MLAP) increased slightly less than cardiac output, reflecting a 20% decrease in pulmonary vascular resistance (Fig. 2). In contrast to the systemic bed, inhibition of cyclo-oxygenase had no effect on pulmonary vascular resistance either at rest or during exercise. NO synthase inhibition produced vasoconstriction in the pulmonary circulation, resulting in an increase in pulmonary artery pressure. Subsequent inhibition of cyclo-oxygenase had no additional effect on pulmonary vascular resistance (Fig. 2).
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Systemic circulation. Administration of the mixed ETA/ETB antagonist tezosentan resulted in a small decrease in aortic blood pressure under resting conditions (Table 1), which was caused by systemic vasodilatation as demonstrated by a decrease of systemic vascular resistance and an increase in mixed venous O2 saturation (Fig. 3). The vasodilator response to tezosentan waned progressively with incremental exercise intensity. Pretreatment with indometacin enhanced the systemic vasodilatation by tezosentan, particularly at rest. In contrast, pretreatment with the NO synthase inhibitor NLA enhanced the vasodilator response to tezosentan both at rest and during exercise. Finally, combined pretreatment with indometacin and NLA caused a further increase in the vasodilator responses to tezosentan (Fig. 3). These observations indicate that both prostanoids and NO blunt the endothelin vasoconstrictor influence in the systemic circulation at rest and during exercise.
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Discussion |
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Pulmonary vascular resistance during exercise
Exercise produced a small decrease in pulmonary vascular resistance, which was probably due to a decrease in vasomotor tone in the pulmonary resistance vessels. Pulmonary vasomotor tone is the resultant of an interplay between vasodilator and vasoconstrictor influences, as is also illustrated by previous findings from our laboratory that 
-adrenoceptor blockade (Stubenitsky et al. 1998) and ET receptor blockade (Merkus et al. 2003) induce pulmonary vasodilatation, while ß-adrenoceptor blockade (Stubenitsky et al. 1998) as well as NO synthase inhibition (Duncker et al. 2000; Merkus et al. 2004) result in pulmonary vasoconstriction in exercising pigs. Importantly, the increase in pulmonary vascular resistance produced by blockade of vasodilator pathways was accompanied by an increase in pulmonary arterial pressure. Since an increase in pulmonary arterial pressure would act to cause a passive decrease in resistance, these studies indicate that the increase in pulmonary vascular resistance must have been the result of an increase in vasomotor tone, and further support the concept that the exercise-induced decrease in pulmonary vascular resistance is principally due to a decrease in pulmonary resistance vessel tone (Dawson, 1984).
Role of endothelium in regulation of pulmonary vascular resistance
Nitric oxide. The role of endogenous NO in maintaining the low basal pulmonary vascular resistance is species dependent. Thus, while the majority of studies suggest a role for NO in the regulation of basal pulmonary vascular resistance in swine, sheep, horses and humans, most studies do not support such a role of NO in dogs (see Hampl & Herget (2000) for references). The role of NO in the pulmonary vasodilatation during exercise is similarly species dependent. Thus, despite causing a significant pulmonary vasoconstriction under resting conditions, NLA had no effect on the exercise-induced pulmonary vasodilatation in sheep (Koizumi et al. 1994) or horses (Manohar & Goetz, 1998). In contrast, we have consistently observed that NO synthase inhibition blunts the exercise-induced pulmonary vasodilatation in swine (Duncker et al. 2000; Merkus et al. 2004). The results of the present study confirm our previous observations and indicate that significant interspecies differences exist with respect to vasomotor control mechanisms within the pulmonary resistance vessels (Hampl & Herget, 2000).
Prostanoids. Inhibition of endogenous prostanoid production does not alter basal pulmonary vascular resistance in sheep (Newman et al. 1986) and swine (Merkus et al. 2004), but causes vasoconstriction in dogs (Lindenfeld et al. 1983; Endredi et al. 1992). In most species, endogenous prostanoids also do not appear to contribute to the exercise-induced pulmonary vasodilatation (Lindenfeld et al. 1983; Newman et al. 1986; Merkus et al. 2004). It could be argued that the dose of indometacin used in the present study was not sufficient to inhibit cyclo-oxygenase in the pulmonary circulation. This is unlikely, however, in view of our observation that indometacin in a dose of 10 mg kg–1 does not produce a greater vasoconstrictor response in the systemic bed than 1 mg kg–1 (Merkus et al. 2004), suggesting a maximal effect. On the other hand, it cannot be excluded that cyclo-oxygenase inhibition may have gone without an apparent effect on pulmonary vascular resistance due to the opposing effects of simultaneously blocking vasodilator and vasoconstrictor prostanoids. Interestingly, the vasoconstrictor response to indometacin in the systemic circulation was enhanced following NO synthase inhibition, which is probably due to the inhibition of prostacyclin synthase activity by NO and peroxynitrite (Zou et al. 1997). In contrast, cyclo-oxygenase inhibition in the presence of NLA still had no effect on pulmonary vascular resistance (Albertini et al. 1996; Merkus et al. 2004), suggesting that prostacyclin activity was not increased following NO synthase inhibition. Future studies, using thromboxane A2 receptor antagonists or thromboxane A2 synthase inhibitors in conjunction with cyclo-oxygenase inhibitors, are required to evaluate in detail the integrated control of pulmonary vascular resistance by vasodilator and vasocontrictor prostanoids during exercise.
Endothelin. ET-induced constriction is mediated by ETA receptors in the large pulmonary arteries, whereas it is mediated by ETB receptors in the smaller pulmonary resistance vessels (MacLean et al. 1994). In accordance with these findings, the density of ETA receptors in the lung decreases with decreasing vessel size, whereas the density of ETB receptors, in both the endothelium and smooth muscle increases (Soma et al. 1999). In our study, blockade of both ETA and ETB receptors did not affect pulmonary vascular resistance at rest, indicating that endo-genous ET does not contribute to resting tone in the pulmonary resistance vessels. During exercise however, an ET-mediated vasoconstriction became apparent, which contrasts with the blunted ET-mediated constriction in the systemic bed (Merkus et al. 2003).
Interactions between NO, prostanoids and endothelin in the regulation of pulmonary vascular resistance
The present study shows that there is an interaction between NO and ET in the pulmonary and the systemic circulation. This interaction was demonstrated by the larger effect on systemic and pulmonary vascular resistance of combined ETA and ETB receptor blockade in the presence of NO synthase inhibition, as compared to the effect of combined ETA and ETB receptor blockade under control conditions. Possible mechanisms behind this interaction include modification by NO of ET production or ET receptor binding affinity (Lavallee et al. 2001; Alonso & Radomski, 2003). Indeed Kelly et al. (2004) showed in vitro, that in pulmonary arterial endothelial cells, NO decreases endothelin-1 secretion through the activation of soluble guanylyl cyclase. Moreover, Wiley & Davenport (2001) showed that NO can modulate the binding of ET to the ET receptor. It has been suggested that the principal vasodilator effect of NO occurs through the inhibition of ET-induced constriction (Lavallee et al. 2001). If this were the case, the level of vasodilatation reached by ET receptor blockade alone would be identical to the level of vasodilatation obtained by the combined effect of ET receptor blockade and NO synthase inhibition. At rest, pulmonary vascular resistance was significantly higher after combined administration of NLA and tezosentan compared to tezosentan alone, which indicates that NO acts predominantly in a direct manner (Fig. 5). However during exercise, pulmonary vascular resistance was only slightly higher (P < 0.05 by ANCOVA) after combined administration of NLA and tezosentan, as compared to administration of tezosentan alone. This suggests that, although a significant part of the vasodilator effect of NO on the pulmonary vasculature during exercise occurs via inhibition of ET, NO also has a direct vasodilator effect on the pulmonary circulation. In the systemic vasculature, the effect of NLA under control conditions is approximately twice as large as the effect of NLA after tezosentan, indicating that the direct vasodilator effect of NO is approximately equal to the vasodilator effect of the NO-mediated inhibition of ET (Fig. 5).
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Clinical relevance
Pulmonary arterial hypertension can arise from a multitude of aetiologies. However, in the later stages of the disease, endothelial dysfunction becomes a central feature (Hampl & Herget, 2000; Budhiraja et al. 2004). Endothelial dysfunction is associated with a loss of endothelial vasodilator substances, including NO and prostanoids. The present study shows that under conditions of endothelial dysfunction, in particular a reduced NO bioavailability, exercise-induced pulmonary vasodilatation is blunted and pulmonary hypertension during exercise is exacerbated, which is due to ‘unopposed’ ET-mediated pulmonary vasoconstriction. These observations support clinical studies that have shown the efficacy of ET receptor antagonism and/or exogenous NO in the treatment of chronic pulmonary arterial hypertension (Hill & Pearl, 1999; Channick et al. 2001; Rubin et al. 2002; Wang et al. 2003).
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P < 0.05 versus NLA.
P < 0.05 effect of Tezo in presence of NLA or NLA + Indo versus effect of Tezo in the presence of Indo; ¶P < 0.05 effect of Tezo in presence of NLA + Indo versus effect of Tezo in the presence of NLA.
